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The Inducible System: Antigens
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The sites on an antigen that are recognized by antibodies (epitopes) may be conformational or sequential (Figure 6.3). A conformational site is any surface shape determined by the complex folding of the molecule. The conformational site is analogous to a mountain range on the surface of the earth which results from continental drift and the crushing together of rock strata. The conformational sites of proteins may be determined by widely separated stretches of amino acid sequences that are brought into proximity by the folding of the polypeptide. Thus, conformational sites are lost with denaturation of molecules, a process which destroys secondary and tertiary structure.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
RNA folding follows a hierarchical pathway analogous to that observed for proteins. The primary base sequence dictates the type of secondary structure formed, which in turn allows the formation of a possible tertiary structure via interaction of preformed secondary structures. Formation of RNA secondary structure dominates the free energy of folding, as each base pair contributes 1–3 kcal/mol of free energy to the final fold. For example, transfer RNAs (tRNAs) have a uniquely evolved tertiary structure, and their primary sequence directs a “clover leaf” secondary structure composed of three stem-loop segments. However, the well-known three-dimensional structure of tRNAs is finalized by the interaction between two of the hairpin loops (the T- and C-loops). This last step, the formation of tertiary structure, contributes only 1.5 kcal/mol of free energy. With regard to small molecule targeting, the secondary structure is generally regarded as the key determinant in defining the “druggability” of a particular RNA.
Protein–Nanoparticle Interactions
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Iseult Lynch, Kenneth A. Dawson
Proteins are chains of amino acids, where the exact sequence of the amino acids determines the protein’s shape, structure, and function. The principle units of protein secondary structure are α-helices and β-sheets, and the three-dimensional arrangement of these is the tertiary structure (α-helix, shown in red, and β-strand, blue, structures are illustrated in Fig. 8.1). The native conformation of a protein is tightly controlled by the shape complementarity of the hydrophobic residues that allow close packing of the cores [28]. Proteins are nevertheless marginally stable because the beneficial interactions that govern the native structure are counterbalanced by a large entropy loss associated with going from a large ensemble of states to a more restricted set of conformations, as well as by the repulsive electrostatic interactions present in the native state [29]. Thus, interaction with a surface can easily disrupt the native conformation and, therefore, the protein function. This has implications for the biological impact of nanoparticles.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Although single-stranded RNA [1] forms complicated secondary structures [2] through classic canonical Watson–Crick base pairing and [3] three-dimensional tertiary structures through non-canonical interactions [4]. Whereas the major and minor grooves of DNA are more accessible to small molecule binding, the major and minor grooves of paired RNA sterically preclude interactions with small molecules [5]. RNA structure is ultimately dictated by the primary ribonucleotide sequence with the base pairing of the primary sequence determining the secondary structure and the internal base pairing of the secondary structure ultimately determining the tertiary structure. In contrast to targeting tertiary or quaternary structures of proteins, targeting RNA with small molecules has largely focused on binding to secondary structures. These secondary structures can be viewed as RNA ‘motifs’ consisting of internal loops (Figure 1(a)), bulges (Figure 1(b)), hairpins (Figure 1(c)), and pseudoknots (Figure 1(d)) in three-dimensional space that are prime candidates for small molecule drug targeting [6,7]. These intricate structures or motifs regulate interactions with RNA-binding proteins and, particularly in the case of noncoding RNAs, such as microRNAs, directly contribute to the biogenesis and functionality of the RNA.
Current trends in the use of human serum albumin for drug delivery in cancer
Published in Expert Opinion on Drug Delivery, 2022
Milan Paul, Asif Mohd Itoo, Balaram Ghosh, Swati Biswas
This process involves using solvent, ethanol, or acetone as a desolvating agent. The solvent is added dropwise into the aqueous albumin solution under stirring conditions until the solution turns turbid. Desolvation changes the proteins tertiary structure and exposes the inner hydrophobic moieties. The structural change in protein causes interaction with other protein molecules via non-covalent interactions, leading to the generation of small, aggregated nanoparticles. Next, the sub-micron particles are stabilized using a chemical cross-linker, such as glutaraldehyde [34]. Reduction of some of the disulfide bridges of native protein molecules before the NPs formation and further promotion of cysteine–cysteine interactions between different HSA molecules could produce NPs without the use of toxic crosslinking agents, such as glutaraldehyde (Figure 2A). Multiple process factors, including concentrations of protein, cross-linker in the solution, amount of desolvating agent, the buffer used, and stirring time and speed, play critical roles in nanoparticle characterization, including particle size, drug loading, entrapment efficiency, and polydispersity [35].
Tracing protein and proteome history with chronologies and networks: folding recapitulates evolution
Published in Expert Review of Proteomics, 2021
Gustavo Caetano-Anollés, M. Fayez Aziz, Fizza Mughal, Derek Caetano-Anollés
At higher levels of organization, striking regularities exist in how secondary structures assemble into tightly packed layered arrangements of the polypeptide chain [54]. These regularities in connectivities and relative orientation of secondary structures (topologies and architectures, respectively), which result in part from physical and chemical properties that are intrinsic [55,56], are responsible for protein tertiary structure. Tertiary structure first manifests in the formation of autonomous folding elements known as protein structural domains (Figure 1A). Domains are structural [57], evolutionary [58] and functional [59] units of proteins, mainly because of their ‘compact globular’ folded structure [first observed by Phillips [60] in lysozyme], their high evolutionary conservation [61] and their recurrent association with molecular functions [62]. Since proteins often contain more than one domain, domains appear repeatedly, individually or combined with other domains sometimes in unusually complex arrangements [5]. This enhances domain recurrence. Tertiary structure also manifests in supradomains, domain combinations that behave as modules and appear recurrently in multidomain proteins [63].